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PubMedDate not supplied

Valine pyrrolidide preserves intact glucose-dependent insulinotropic peptide and improves abnormal glucose tolerance in minipigs with reduced beta-cell mass.

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are important in blood glucose regulation. However, both incretin hormones are rapidly degraded by the enzyme dipeptidyl peptidase IV (DPPIV). The concept of DPPIV inhibition as a treatment for type 2 diabetes was evaluated in a new large animal model of insulin-deficient diabetes and reduced beta-cell mass, the nicotinamide (NIA) (67 mg/kg) and streptozotocin (STZ) (125 mg/kg)-treated minipig, using the DPPIV inhibitor, valine pyrrolidide (VP) (50 mg/kg). VP did not significantly affect levels of intact GLP-1 but increased levels of intact GIP (from 4543 +/- 1880 to 9208 +/- 3267 pM x min; P <.01), thus improving glucose tolerance (area under the curve [AUC] for glucose reduced from 1904 +/- 480 to 1582 +/- 353 mM x min; P =.05). VP did not increase insulin levels during the oral glucose tolerance test (OGTT) but increased the insulinogenic index in normal animals (from 83 +/- 42 to 192 +/- 108; P <.05), but not after NIA + STZ, possibly because of less residual insulin secretory capacity in these animals. GIP seems to contribute to the antihyperglycemic effect of VP in this model; however, additional mechanisms for the effect of DPPIV inhibition cannot be excluded. The authors conclude that DPPIV inhibitors may be useful to treat type 2 diabetes, even when this is due to reduced beta-cell mass.

Animals↗
PubMedDate not supplied

Metabolic effect of short-term total parenteral nutrition highly enriched with leucine or valine in rats recovering from severe trauma.

The metabolic impact of infusing a large amount of leucine (Leu) or valine (Val) was examined with regard to the corrective effect of total parenteral nutrition (TPN). Rats recovering from severe sepsis received either Leu- or Val-enriched TPN solution for 30 hours. The in vivo behavior of the amino acids administered was explored by a pulse injection of 14C-labeled Leu or Val. The recovery of 14CO2 from Leu increased by 64% in the septic rats of Leu-TPN group (41% of dose; p less than .01), as compared with control rats receiving the same TPN solution, whereas no significant rise in the 14CO2 recovery from Val occurred in the septic rats given Val-TPN (45% of dose) in comparison with the corresponding controls. The enhancement of Leu catabolism to CO2 in the Leu-TPN group was compatible with the alterations of urinary nitrogen excretion, plasma Leu level, and metabolite contents of liver and muscle. The only difference in metabolite levels observed between the two TPN groups was in hepatic total adenine nucleotides. Plasma amino acid levels were largely unaffected by infusion of these TPN solutions highly enriched with branched-chain amino acids (45%), except for an approximately threefold elevation of the Val level in Val-TPN rats. Thus, when administered in a large quantity during such short-term TPN, Leu can exert its metabolic effect without causing an imbalance in plasma amino acids under severe catabolic conditions.

Amino Acids↗
PubMed2003

Pharmacokinetic evaluation of 3'-azido-2', 3'-dideoxyuridine-5'-O-valinate-hydrochloride as a prodrug of the anti-HIV nucleoside 3'-azido-2', 3'-dideoxyuridine.

3'-Azido-2', 3'-dideoxyuridine (AZDU, AzddU, CS-87) has been shown to have potent anti-HIV activity in vitro. However, the compound exhibits a relatively short half-life and incomplete oral bioavailability in humans. In an effort to improve the pharmacokinetic properties of AZDU, prodrug 3'-azido-2',3'-dideoxyuridine-5'-O-valinate hydrochloride (AZDU-VAL) was synthesized by the esterification of 5'-OH function in AZDU. The objective of this study was to investigate the biotransformation and pharmacokinetics of AZDU-VAL along with its antiviral parent compound AZDU following intravenous and oral administration to rats. Adult male Sprague-Dawley rats were administered AZDU or AZDU-VAL by intravenous injection or oral gavage. Concentrations of AZDU-VAL and AZDU were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis. The bioavailability of AZDU after oral administration was approximately 53%. The terminal phase half-life of the nucleoside analogue ranged between 0.6 h after intravenous administration and 1 h following oral administration. In vivo the prodrug was rapidly and efficiently biotransformed to yield AZDU following intravenous and oral administration. The apparent availability of AZDU was virtually complete following oral administration of prodrug AZDU-VAL averaging 101%. The bioavailability of AZDU following intravenous administration of AZDU-VAL averaged 106%. In summary, the disposition of AZDU was dose dependent over the dose range of 25-100 mg/kg. Renal clearance and steady state volume of distribution were lower at the higher dose level. Prodrug AZDU-VAL demonstrated improved oral bioavailability as evidenced by complete absorption and efficient bioconversion to AZDU. The results suggest that AZDU-VAL may be a promising prodrug for the delivery of AZDU.

Administration, Oral↗
PubMed1982

Reduction of cerebrospinal fluid phenylalanine after oral administration of valine, isoleucine, and leucine.

A supplement of the branched chain amino acids, valine, isoleucine, and leucine (VIL) was administered orally to patients with phenylketonuria, either together with unrestricted diet of natural protein or with a low phenylalanine diet. The VIL supplement brought about a significant reduction of the cerebrospinal fluid-serum ratio of phenylalanine from a mean value of 0.254 without VIL to 0.204 with VIL. The reduction varied from 15-40% (mean 21%). Concentrations of glycine, lysine, methionine, threonine, tryptophan, and tyrosine were within normal limits in serum and cerebrospinal fluid of infants with phenylketonuria. No amino acid imbalance was created by the supplement and no adverse effects from VIL were observed.

Administration, Oral↗
PubMed2005

The valine allele of the V89L polymorphism in the 5-alpha-reductase gene confers a reduced risk for hypospadias.

CONTEXT: Hypospadias is one of the most common malformations in man, with an incidence of 1:300 in newborn boys. No gene has been identified that causes isolated hypospadias, but the androgenic influence is important during male genital development. OBJECTIVE: A key enzyme for the androgenic function is steroid 5-alpha-reductase (SRD5A2). The V89L polymorphism in the SRD5A2 gene has been studied and found to be of functional importance. The leucine version of the enzyme is 30% less efficient than the valine variant. DESIGN, SETTING, PATIENTS, AND RESULTS: We have genotyped 158 hypospadias cases and 96 unaffected controls for this polymorphism and found a significant negative association for the V89 allele in hypospadias (odds ratio, 0.24; 95% confidence interval, 0.14-0.41 for homozygous individuals). This indicates that a fully functional 5-alpha-reductase enzyme (homozygous for V89) protects the male urethral development. This association is shown regardless of heredity, ethnicity, and severity of phenotype. We have also sequenced a selected material of 37 sporadic cases of more severe hypospadias for mutations in the androgen receptor AR, SRD5A2, and 17beta-hydroxysteroid dehydrogenase HSD17B3 genes and found only two previously described mutations, one in the AR and one in the SRD5A2 gene. CONCLUSION: This finding is in accordance with the assumption that functional polymorphisms may play an important role in complex disorders such as hypospadias when several genes as well as environmental factors contribute to the etiology.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1993

A glycine-1008 to valine mutation in the insulin receptor in a woman with type A insulin resistance.

We examined the insulin receptor gene in a Japanese woman with type A insulin resistance. Acanthosis nigricans and polycystic ovary were present. A 75-g oral glucose tolerance test showed a diabetic pattern, and fasting insulinemia was 780 pmol/L. Insulin binding was normal, but autophosphorylation and tyrosine kinase activity were reduced in partially purified insulin receptors from Epstein-Barr virus-transformed lymphocytes. The nucleotide sequence for all 22 exons of the insulin receptor gene was determined by direct sequencing of genomic DNA amplified with the polymerase chain reaction. Substitution of valine for glycine at codon 1008 in the tyrosine kinase domain was identified in one allele. This was the same mutation found in another patient, but there was no relationship between the two families. The father had the same mutation in one allele and impaired glucose tolerance with mild hyperinsulinemia, but the mother and two brothers had normal glucose tolerance. We conclude that a single mutant allele in the tyrosine kinase domain caused the insulin resistance.

Adult↗
PubMed1995

Selective use of L-valine and L-isoleucine for the biosynthesis of branched-chain fatty acids in rat skin.

Iso- and anteiso-fatty acids are detected in more than trace amounts in rat skin surface lipid. The terminal portion of even carbon number iso- and anteiso-fatty acids are synthesized respectively from valine (Val) and isoleucine (Ile) by essentially the same reaction sequences established for straight chain fatty acids. This paper describes the stereospecific biosynthesis of these branched chain fatty acids (BCFAs) and alcohols (BCFALs) in rat skin. Dependence of the concentration of these BCFAs on dietary L-Val and L-Ile was studied. Concentrations of even carbon number iso- and anteiso-fatty acid increased respectively with dietary L-Val and L-Ile. The saturation dose appeared to be 2% for L-Val and 1% for L-Ile. Supplementation of the diet with 2% D-Val, however, did not affect the concentration of even carbon number iso-fatty acid in rat skin surface lipid despite a comparable serum Val level to that of the 2% L-Val group. A similar experiment using 1% DL-Ile found that L-isomer, but not D-isomer, in the circulation was used for the biosynthesis of anteiso-fatty acids. This view was applicable to the incorporation of D-Val and DL-Ile into related BCFALs.

Absorption↗
PubMed1984

Metabolism of 2-oxo-acid analogues of leucine and valine in isolated rat hepatocytes.

Isolated hepatocytes were incubated with 1-14C-labelled 2-oxo-acid analogues of leucine and valine. Decarboxylation and transamination rates were determined by measuring 14CO2 release and the appearance of the corresponding 14C-labelled amino acid. Decarboxylation exceeded transamination with both substrates, the ratio of decarboxylation/transamination being 3.4 for 4-methyl-2- oxovalerate and 78 for 3-methyl-2-oxobutyrate. Urea synthesis and ammonia utilization were not significantly decreased by the 2-oxo-acids even under conditions of stimulated urea production. To see if dietary treatment can alter the decarboxylation/ transamination ratio in favour of transamination rats were fed diets low in nitrogen content. These diets caused a reduction of the branched-chain 2-oxo-acid dehydrogenase activity by 80% but did not alter the branched-chain amino-acid aminotransferase activity in liver cells. This change in enzyme activities resulted in a marked decrease of the uptake and decarboxylation rates of 4-methyl-2- oxovalerate but did not enhance the conversion to the corresponding amino acid. Reducing the uptake of branched-chain 2-oxo acids by liver might increase the amount of orally administered 2-oxo acids reaching the muscle for transamination thus improving the nitrogen-sparing effect of these compounds.

Ammonia↗
PubMed1993

Glycine-rich analogues of Cucurbita maxima trypsin inhibitor (CMTI-III) substituted by valine in position 27 display relatively low antitrypsin activity.

Five new analogues of the trypsin inhibitor CMTI-III were synthesized by the solid-phase method. All analogues containing a valine residue in position 27 and glycine residues in some or all of the positions 9, 11, 14, 17, 19, 29 as well as in two cases a norleucine residue in position 8 displayed association equilibrium constants by 6-7 orders of magnitude lower than the native CMTI-III inhibitor.

Amino Acid Sequence↗
PubMed1995

A mixture of the branched chain amino acids leucine, isoleucine and valine increases ovulation rate in ewes when infused during the late luteal phase of the oestrous cycle: an effect that may be mediated by insulin.

The positive relationship between nutritional state and ovulation rate in sheep may involve the action of specific nutrients on gonadotrophin release. LH and FSH secretion is controlled in part by hypothalamic GnRH, which is in turn influenced by central adrenergic and serotonergic neuronal systems. In this experiment the branched chain amino acids (BCAAs) leucine, isoleucine and valine were examined for effects on LH and FSH secretion. A mixture of the three amino acids was infused into ewes for 5 days immediately before luteolysis, a time when nutritional effects on ovulation rate occur. The infusion significantly increased ovulation rate without any associated increase in FSH or LH. However, the infusion did increase plasma insulin concentrations and this effect, together with the high levels of blood urea observed, suggests that these amino acids had increased the supply of energy substrates to the follicles. An increase in insulin-mediated glucose uptake by follicles could be the stimulus responsible for the increase in ovulation rate. The ability of the animal to utilize BCAAs for energy metabolism may be an important component of the ovulation responses to nutrition.

Amino Acids, Branched-Chain↗
PubMed2001

Elevation of N-(carboxymethyl)valine residue in hemoglobin of diabetic patients. Its role in the development of diabetic nephropathy.

OBJECTIVE: Advanced glycation end products (AGEs) are a risk factor for diabetic complications. We have developed an assay method for N-(carboxymethyl)valine (CMV) of the hemoglobin (CMV-Hb), which is an AGE generated from HbA1c. Herein we describe the clinical utility of CMV-Hb measurement for the diagnosis of diabetic nephropathy RESEARCH DESIGN AND METHODS: BALB/c mice were immunized with carboxy-methylated Hb and monoclonal antibody raised against CMV-Hb. This antibody was characterized by a surface plasmon resonance. We developed a latex immunoassay using the antibody and measured CMV-Hb from erythrocytes in type 2 diabetic patients and healthy control subjects (age 64.6 +/- 12.0 vs. 61.1 +/- 13.2 years, NS: HbA1c 69 +/- 1.5 vs. 5.2 +/- 0.4%, P < 0.0001). RESULTS: A monoclonal antibody against CMV-Hb beta-chain NH2-terminal and an assay method for measurement for CNMV-Hb were both developed in our laboratory. CMV-Hb levels were significantly greater in the diabetic patients than in the control subjects (18.2 +/- 6.9 vs. 12.7 +/- 0.9 pmol CMV/mg Hb, P < 0.0001). No correlation was found between CMV-Hb and HbA1c or CMV-Hb and glycated albumin. Levels of CMV-Hb increased as the diabetic nephropathy progressed. CONCLUSIONS: We established an assay method for CMV-Hb and confirmed the presence of CMV-Hb in circulating erythrocytes. CMV-Hb was more prevalent in diabetic patients than in healthy subjects. Furthermore, it was significantly higher in patients with diabetic nephropathy, suggesting that the presence of CMV-Hb may be a valuable marker for the progression of diabetic nephropathy.

Animals↗
PubMed1982

Metabolism of methyl methacrylate: evidence for metabolism by the valine pathway of catabolism in rat and in man.

1. Evidence to support the suggestion that methyl methacrylate is metabolized by the normal pathway of valine catabolism has been obtained by the administration of methyl [Me-14C]methacrylate to rats. 2. Of the administered dose, 80% was respired as 14CO2 as predicted, and methylmalonic acid, specifically labelled with 14C in a manner consistent with the proposed pathway of metabolism, was excreted (0.22%) dose). 3. Following administration of sodium [Me-2H3]methacrylate to a human subject, [Me-2H3]methylmalonic acid was detected in the urine by g.l.c.-mass spectrometry.

Animals↗
PubMed1981

Hemoglobin Tottori (alpha 59[E8] glycine replaced by valine).

A new electrophoretically silent, unstable hemoglobin was discovered in a Japanese family. Isolation of the abnormal chain and chemical analyses demonstrated a previously unreported amino acid substitution, alpha 59[E8] glycine replaced by Valine. The new variant has been named Hb Tottori.

Adult↗
PubMed1990

Dietary requirements of leucine, isoleucine, and valine in male broilers during the starter period.

Growth studies were conducted with 3-wk-old, male broiler chicks to determine their requirements for the branched-chain amino acids (BCAA) leucine, isoleucine, and valine during the starter period. The central-composite, rotatable design was applied. The data were analyzed using regression methodology. The results showed that the linear term of Leu and the cross-product terms of Leu with Ile or Val were nonsignificant (P greater than .05). Second-order equations described the relationship between the BCAA, weight gain (WG), and feed conversion (FC). The coefficient of determination values indicated that 80% or more of the variation in WG and FC was explained by the polynomial equations. The results suggested that the Leu requirement does not exceed 1.16% of a diet calculated to contain 3,200 kcal of metabolizable energy per kilogram. The optimum response, maximum in the case of WG (444 g) and minimum for FC (1.40), would be obtained by feeding a diet containing 1.16, .80, and .90% of Leu, Ile, and Val, respectively. The values of Ile and Val are the actual values obtained when the diets were hydrolyzed for 72 hours. For Leu, however, the hydrolysis time was 24 hours.

Animal Feed↗
PubMed1987

Asymmetric synthesis of L-2-amino[3-11C]butyric acid, L-[3-11C]norvaline and L-[3-11C]valine.

The short-lived radionuclide 11C (t1/2 = 20.4 min) has been used in the asymmetric synthesis of L-2-amino[3-11C]butyric acid, L-[3-11C]-norvaline and L-[3-11C]valine. The syntheses were performed by alkylation of [(+)-2-hydroxypinanyl-3-idene]-glycine tert-butyl ester under anhydrous conditions in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone with lithiated 2,2,6,6-tetramethylpiperidine as base, using the appropriate 11C-alkyl iodides prepared in a one-pot reactor from [11C]carbon dioxide. Following removal of the protecting groups, the -[3-11C]amino acids were obtained in 80-82% enantiomeric excess and in 9-25% radiochemical yields, decay corrected and calculated on the basis of the amount of [11C]carbon dioxide at the start of the syntheses within 50-55 min.

Alkylation↗
PubMed1999

A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.

Aged↗
PubMed2002

Concentrations of branched amino acids: isoleucine, valine, leucine in serum of hemodialysis patients during one-year observation.

Malnutrition is commonly reported in haemodialysis patients (HD pts) and is multifactorial in origin. Previous studies indicated a possible relationship between plasma levels of branched-chain amino acids (BCAA): isoleucine, leucine, valine and nutritional status of HD pts. The BCAA have important influence on metabolism of energy in skeletal muscles, in addition the leucine makes easy the synthesis of protein. In the present investigation we evaluated some parameters of nutritional state and the concentration of branched-amino acids in haemodialysis patients during one-year observation. Sixty-seven patients undergoing haemodialysis were assessed in the first study (study I), after 12 months this assessment was repeated in 70 patients (study II). Blood was drawn before the midweek dialysis session. Morphology, plasma albumin concentration and urea for KT/V calculation were determined by routine methods. Branched amino acids were measured by chromatography method with amino acid analyser AAA 400, using a lithium-citric buffer system. The plasma amino acid pattern was measured in the study group and compared with 20 healthy persons. Mean amino acids concentration observed in both study groups was significantly lower than in the control group. Mean concentration of BCAA was also lower than in control group. There was a small negative correlation between albumin concentrations and the length of dialysis therapy. There were significant positive correlations between: total amino acids, branched amino acids as well as albumin, especially in study II.

Adult↗